The goals of this SPORE in Thyroid Cancer are to leverage new insights on disease pathogenesis to improve the outcome of patients with thyroid cancer at all stages of presentation. Our translational research objectives are: TR01: To explore how to implement a more rational care of patients with papillary microcarcinomas (PMC), which are highly prevalent and overtreated in the community, leading to unacceptable morbidity and wasteful health care expenditures. We propose to identify genetic predictors of progression in archival specimens and through a prospective observational study of patients with PMC left in situ, which will provide evidence-based guidelines for care. TR02: To improve the effectiveness of radioiodine (RAI) therapy in patients with RAI-refractory metastatic thyroid cancer based on new insights on the role of MAPK signaling in downregulating iodine transport and incorporation into cancer cells. TR03: To identify new approaches to treat patients with life-threatening metastatic thyroid cancer, using targeted therapies designed against key drivers of the disease, and by implementing strategies to overcome adaptive resistance mechanisms triggered by blocking key oncogenic pathways. To meet these objectives, we will undertake four main projects with the following titles: RP1: Genomic predictors of PMC disease progression. RP2: Maximizing effectiveness of radioiodine therapy by inhibiting MAPK signaling. RP3: Elucidating and targeting the molecular foundations of Hurthle cell cancer. RP4: Molecular landscape-based innovative therapies for anaplastic thyroid carcinoma. Our Developmental Research Program counts with strong candidate pilot projects, which document the robust pipeline of investigators interested in this disease, and an outstanding group of scientific advisors who will help identify and select the best projects for funding. The Career Development Program will take advantage of the strong training environment in the clinical and scientific programs at our institutions to identify and promote the research and training of young investigators focused on translational research in thyroid cancer. The SPORE will be supported by three Core facilities: CFA: Biospecimen Repository. CPB: Biostatistics. CFC: Administration.